Encephalitis caused by Coxiella burnetii.

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The only abnormality noted in teased-fiber preparations from Patient 3 was wallerian degeneration found
in a single fiber (out of 33 fibers examined). In Patients
1 and 2, short and long segments of demyelination
were present (in 10 to 15% of the fibers) (Figure, C) as
well as remyelinated segments (2.5 to 10% of the
fibers) and rare wallerian degeneration.
Discussion
CTX is an autosomal recessive disorder usually manifesting in early childhood with mental retardation. As
it progresses, further neurological dysfunction becomes evident [l, 3, 5-7). The three siblings reported
here had the clinical features typical of CTX-tendon
xanthomas, early cataracts, mental retardation, and
neurological syndrome characterized by spinocerebellar disorder and seizures. Biochemical studies demonstrated excessive cholestanol levels in the serum,
confirming the diagnosis of CTX.
The unusual feature in our patients was the PNS
involvement. Clinical findings were not typical of peripheral neuropathy. Although mild distal muscular atrophy and pes cavus were present, DTRs were hyperactive, and only minimal abnormalities in vibration
sensation were noted.
The electrophysiological findings were thus unexpected. Motor NCVs ranged between 12 and 34 d s e c
in the legs, and sensory nerve action potentials were
reduced or absent. These findings combined with the
lack of active denervation of muscle indicate a primarily demyelinating neuropathy. Sural nerve biopsies
confirmed the demyelinating nature of the neuropathy
and further demonstrated the prominent onion bulb
formations considered indicative of recurrent demyelination and remyelination [S].
Slowed NCVs were reported by Kuritzky et a1 CZ]
in four patients with CTX, but only two of them had
evidence of widespread PNS involvement similar to
our patients. The authors did not report EMG or
nerve biopsy findings and were not conclusive about
the demyelinating nature of the disorder. Excessive
demyelination and remyelination with occasional onion bulbs were reported by Ohnishi et al [4] in a patient with CTX who had no clinical or electrophysiological evidence of neuropathy.
Demyelinating neuropathy is probably a part of the
CTX syndrome and should be looked for even if clinical features of neuropathy are inapparent. We also suggest that cerebrotendinous xanthomatosis be added to
the differential diagnosis of recessively inherited demyelinating neuropathies.
The authors thank Dr K. Fried of Ass& Harofeh Hospital for referring the patients and Dr G. Salen for performing cholestanol
determinations.
References
1. Bhattacharyya AK, Connor WE: Familial diseases with storage of
2.
3.
4.
5.
6.
7.
8.
sterols other than cholesterol. In Stanbury JB, Wyngaarden JB,
Fredrickson DS: The Metabolic Basis of Inherited Disease, ed 4.
New York, McGraw-Hill, 1978, pp 656-669
Kuritzky A, Berginer VM, Korczyn AD: Peripheral neuropathy
in cerebrotendinous xanthomatosis. Neurology (NY) 29:880881, 1979
Menkes JH, Philippart M: Cholestanol storage in the nervous
system of two patients with cerebrotendinous xanchomatosis.
Trans Am Neurol Assoc 93:66-68, 1968
Ohnishi A, Yamashita Y , Goto I, et al: De- and remyelination
and onion-bulb in cerebrotendinous xanthomatosis. Acta Neuropathol (Berl) 45:43-45, 1979
Phiilippart M, vanBogaert L Cholestanolosis (cerebrorendinous
xanthomatosis). Arch Neurol 21:603-610, 1969
Salen G, Shefer S, Berginer VM: Familial diseases with storage of
sterols other than cholesterol. In Stanbury JB, er al: The Metabolic Basis of Inherited Disease, ed 5. New York, McGraw-Hill,
1983, pp 713-724
Schimschock JR, Ellsworth CA, Swanson PD: Cerebrotendinous
xanthomatosis. Arch Neurol 18:688-698, 1968
Thomas PK, Lascelles RC: Hypertrophic neuropathy. Q J Med
36:223-238, 1967
Encebhahtis Caused
Robert G. Brooks, MD,* Carmelo M. Licitra, MD,?
and Marius G. Peacock$
~~~
Acute infection with Coxiella burnetii usually results in
a self-limited illness, but: it can occasionally cause
chronic endocarditisor hepatitis. Headache is a common
presenting symptom of acute infection with this agent,
but specific neurological abnormalities are rare. We report the case of a patient with acute Q fever that caused
frank encephalitis. We also review the literature on central nervous system disease attributable to C . burnetii.
Brooks RG, Licitra CM, Peacock MG:
Encephalitis caused by Coxiella burnetii.
Ann Neurol 20:91-93, 1986
Q fever is generally regarded as an acute self-limited
febrile illness, often with mild respiratory symptoms in
association with malaise, myalgias, and headache [I, 2,
7, 9, lo]. Disease of the central nervous system has
been rare El, 9, 101and has most often been seen with
From the "Department of Internal Medicine, Division of Infectious
Diseases, Stanford University, Stanford, CA, the tDepartment of
Internal Medicine, Orlando Regional Medical Center, Orlando, FL,
and the $Epidemiology Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT.
Received Aug 26, 1985, and in revised form Oct 16. Accepted for
publication Nov 23, 1985.
Address reprint requests to Dr Brooks, Department of Internal
Medicine, Orlando Regional Medical Center, Orlando, FL 32806.
Re.cults of Serological Tests on a Patient with Encephalitis Caused by Coxiella burnetii
Microagglutination
Microimmunofluorescence
Complement
Fixation
IgG
-
IgM
IRA
_
.
Date
ph I1
Ph 1
phlI
phl
phII
Ph I
phll
phl
phII
phl
512"
1,024
512
256
5 12
512
1,024
256
256
256
128
512
256
64
64
32
128
64
32
32
512
1,024
512
64
128
256
256
128
64
64
128
256
512
64
64
128
128
32
32
64
534,288
13 1,072
524,288
65,536
2,048
1,024
16,384
8,192
4,096
4,096
13 1,072
262,144
262,144
32,768
4,096
512
8,192
4,096
1,024
1,024
128
64
64
64
16
16
64
16
16
16
128
256
128
256
32
10
128
16
8
16
16
16
256
32
<8
<8
<8
512
2,048
1,024
2,048
128
128
128
64
128
64
<4
4
ND
ND
ND
ND
128
256
32
64
<8
<8
<8
<8
<8
<8
<8
<8
<4
ND
ND
<8
<8
<8
<8
<8
<8
SERUM
~
4125184
5/24/84b
612 1/84b
8/02/84
9/06/84
10117/8/1
1/29/85
3118185
4/06/85
5/16/85
<R
<8
<8
CEREBROSPINAL FLUID
4/25/84'
<4
51 ~ 1 8 4 ~ 4
URINE
6121184"
<4
"Reciprocal of titer.
'Attempts made to culture C. burnerii were unsuccessful.
ph I, I1 = phase of C. burnetii antigen used; ND = not done.
endocarditis caused by Coxiella burnetii [4, 61. We report the case of a patient with probable Q fever endocarditis that presented as acute encephalitis; we also
review the literature on central nervous system disease
caused by this rickettsial organism.
Case Report
A 34-year-old white man was admitted to the hospital on
March 4, 1984, because of marked disorientation and confusion. Six weeks before admission he had been seen by a
private physician with cough, low-grade fever, and myalgias.
He had been given a 7-day course of oral cephalexin. Fever
had persisted and he was therefore treated with oral trimethoprim and sulfamethoxazole twice a day for 10 days.
The day before hospitalization the patient was noted to be
somewhat irritable, glassy-eyed, and mildly disoriented.
Upon awakening the following morning he was found to be
agitated and disoriented, he was taken to the emergency
room, where grand mal seizures began.
His medical history was normal except for rheumatic fever
during childhood. He was employed as a salesman and had
had no specific exposure to livestock or other animals.
Physical findings o n admission included a temperature of
37.7"C, a Grade IV/VI systolic murmur heard best in the
aortic area, and the absence of focal neurological abnormalities. His peripheral white blood cell count was 19,4001
mm3, with 3 1% polymorphonuclear leukocytes, 1% band
forms, 75% monocytes, and 61% lymphocytes, A computerized tomographic scan of the head showed narrowed
92 Annals of Neurology Vol 20 N o 1 July 1986
sulci but no midline shift or focal abnormalities. Lumbar
puncture revealed 72 white blood celldmm3 (100% lymphocytes), a protein level of 102 mg/dl, and a glucose level of 67
mgldl. An electroencephalogram showed a moderately severe generalized cortical dysfunction (dysrythmia Grade Ill)
but no focal abnormalities.
An echocardiogram revealed a calcified aortic valve with
no evidence of vegetations. Because of the concern about
endocarditis, however, blood cultures were drawn and the
patient was given intravenous nafcillin, cefotaxime, and tobramycin. Repeat lumbar puncture performed because of
persistent headache 10 days after admission was normal. The
patient's fever and neurological condition improved rapidly
in the hospital and he was discharged on April 1, 1984, after
having received approximately 2 weeks of intravenous antibiotic therapy.
The patient did well until 3 weeks later, when he experienced an acute onset of photophobia, diffuse headache, and
low-grade fever. He was admitted to the hospital and
reevaluated for encephalitis. A computed tomographic scan
of the head and an electroencephalogram were normal. Lumbar puncture revealed an opening pressure of 230 m m H 2 0 ,
79 white blood cellslmm3 (100% polymorphonuclear leukocytes), a protein level of 85 mg/dl, and a glucose level of 54
mgidl. An echocardiogram was unchanged. Serum for antibody titer to C. burnetii was drawn as part of the evaluation
for culture-negative endocarditis and a complement fixation
titer of more than 1: 5 12 (using combined Phase I and Phase
I1 antigen) was reported. Further serological evaluation
(Rocky Mountain Lab, NIAID) is shown in the Table. At-
tempts t o isolate C. burnetii by inoculation of cerebrospinal
fluid, blood, and urine into egg yolk sacs and meadow voles
[S] yielded negative results. Doxycycline (200 mg/day) was
begun and no further neurological o r cardiac sequelae have
been noted after 12 months of follow-up.
Discussion
Headache is a common symptom in acute Q fever,
with an incidence of 80 to 100% reported in most
series [l, 5, 7, 9, lo}. Eight of 9 patients reported in
Derrick‘s [Z] original paper on Q fever were first seen
with headache that was “severe, intense, and raging.”
However, other signs and symptoms referable to the
central nervous system are rare in infections caused by
C. burnetii. Focal neurological deficits have not been
found as a result of the acute primary infection, and
when present have most commonly been caused by
emboli from endocarditis C4, 63. Signs of diffuse meningeal irritation, however, have been reported by several authors [ 3 , 6, 9}. In a review of 72 consecutive
cases of Q fever, Powell 193 reported 8 cases (11%) of
neck stiffness, which was moderarely severe in 6 and
marked in 2 patients. Extrapyramidal neurological
signs, including cogwheel rigidity and an intention
tremor of the upper extremities, were reported by
Gallagher [SI in a 46-year-old patient with Q fever
hepatitis. This patient also had periods of mental confusion during high fever.
An acute confusional state such as that seen in our
patient has been noted in several additional patients [l,
93. Confusion occurred in 2 cases reported by Powell
[9]. One was a man who had clinical jaundice and
pneumonia, but had no physical examination or cerebrospinal fluid evaluation to support a diagnosis of encephalitis. The second was a patient with known
seizure disorder who had been off his usual anticonvulsant drugs; his confusion appeared to be associated with the postictal state. In addition to these 2
patients, Buckley [l] reported the case of a 17-yearold who was first seen with headache, high fever, and
depressed state of consciousness, but no mention of
further neurological deficits or cerebrospinal fluid
findings was made. The patient reported on here, however, appears to be the first in whom encephalitis was
documented by clinical findings (confusion, agitation,
and generalized seizures), abnormalities of computed
tomographic scan and electroencephalogram, and persistent cerebrospinal fluid abnormalities.
The mechanism by which infection with C. burnetii
may cause signs and symptoms attributable to the central nervous system is not known. Isolation of C. burnetzi has been reported from the spinal fluid in l patient with Q fever who had meningitis and encephalitis
[SJ. Other mechanisms of injury, such as that mediated
by immune complexes [7}, may also be of importance
in the production of neurological signs or symptoms.
We may have been unable to culture the organism
from cerebrospinal fluid, blood, or urine because samples were taken late after the onset of the patient’s
symptoms or because the patient had recently received
a course of antimicrobial therapy. Despite the lack of a
positive culture, it is very likely that our patient had Q
fever endocarditis, based on the serum antibody titers
against both Phase I and Phase I1 antigens 181. Phase I
surface component antigen is less immunogenic than
the masked Phase I1 antigen, but patients in whom
persistent or recrudescent infection leads to chronic
disease have greatly increased anti-Phase I titers,
probably because of constant antigenic stimulation.
The presence of high titers of IgA antibody, such as
those seen in our patient, is considered diagnostic of
endocarditis caused by C. burnetii IS]. Cross-reactivity
of C. barnetii antigens with other rickettsial or bacterial
antigens has not been observed.
Although diagnosis of systemic Q fever can be
verified by serum serological analysis, verifying the etiological role of this agent in a patient seen with
neurological signs or symptoms is difficult. Results of
lumbar puncture are often normal in patients seen with
headache alone 13, 91. When signs of meningismus or
encephalitis are present, however, lumbar puncture
should be performed. Our patient had abnormal cerebrospinal fluid findings on several occasions, corresponding to his clinical episodes of encephalitis. An
epidemiological history suggestive of Q fever is not
always obtained (as in our patient) and therefore cerebrospinal fluid and serum serological analysis, and cultures for C. bzlrnetii, may need to be performed in
patients with encephalitis of unknown cause.
References
1. Buckley B: Q fever epidemic in Victorian general practice. Med
J Aust 1:593-595, 1980
2. Derrick EH: “ Q fever a new fever entity: clinical features,
diagnosis and laboratory investigation. Med J Aust 2:281-299,
1937
3. Ellis ME, Dunbar EM: In vivo response of acute Q fever to
erythromycin. Thorax 37:867-868, 1982
4. Ellis ME, Smith CC, Moffat MAJ: Chronic or fatal Q-fever
infections: a review of sixteen patients seen in northeast Scotland (1967-80). Q J Med 205:54-66, 1983
5. Gallagher WH: Q-fever. JAMA 177:187-189, 1961
6. Kimbrough RC, Ormsbee RA, Peacock M, et al: Q-fever endocarditis in the United States. Ann Intern Med 91:400-402,
1979
7. Lumio J, Pentinen K, Pettersson T: Q-fever in Finland: clinical,
immunological and epidemiological findings. Scand J Infect Dis
13:17-21, 1981
8. Peacock MG, Philip RN, WilliamsJC, Faulkner RS: Serological
evaluation of Q fever in humans: enhanced Phase I titers of
immunoglobulins G and A are diagnostic for Q fever endocarditis. Infect Immunol 41:1089-1098, 1983
9. Powell 0: “Q’ Fever: clinical features in 72 cases. Aust Ann
Med 9:214-223, 1960
10. Spelman DW: Q fever: a study of 111 consecutive cases. Med J
Aust 1:547-553, 1982
Brief Communication: Brooks et al: Encephalitis Due to C. burnetii 93